SP and IL-33 together markedly enhance TNF synthesis and secretion from human mast cells mediated by the interaction of their receptors.

The peptide substance P (SP) and the cytokine tumor necrosis factor (TNF) have been implicated in inflammatory processes. Mast cells are recognized as important in inflammatory responses. Here, we report that IL-33 (30 ng/mL), a member of the IL-1 family of cytokines, administered in combination with SP (1 µM), markedly increase (by 1,000-fold) TNF gene expression in cultured human LAD2 and primary mast cells derived from umbilical cord blood. SP (0.01-1 µM) and IL-33 (1-100 ng/mL) in combination also greatly stimulate TNF secretion (by 4,500-fold). Pretreatment of LAD2 cells with two different neurokinin-1 (NK-1) receptor antagonists and siRNA inhibits TNF secretion by 50% (P < 0.001) when stimulated by SP and IL-33. Pretreatment of LAD2 cells with a neutralizing antibody for IL-33 receptor, ST2, inhibits TNF secretion by 50% (P < 0.001), and ST2 siRNA decreases TNF secretion by 30% (P < 0.05), when stimulated by SP and IL-33. Surprisingly, NK-1 antagonists also inhibit 50% of TNF secretion (P < 0.001) when stimulated only by IL-33, and ST2 receptor reduction also decreases SP-stimulated TNF secretion by 30% (P < 0.05), suggesting an interaction between NK-1 and ST2 receptors. Moreover, IL-33 increases NK-1 gene and surface protein expression, as well as IKß-α phosphorylation. Pretreatment of LAD2 cells with 5,7,3',4'-tetramethoxyflavone (methoxyluteolin) (1-100 µM) inhibits (P < 0.001) TNF gene expression (98%) and secretion (64%) at 50 µM and phosphorylation of p-IKB-α at 1 µM when stimulated by SP and IL-33. These findings identify a unique amplification process of TNF synthesis and secretion via the interaction of NK-1 and ST2 receptors inhibitable by methoxyluteolin.

Stress triggers coronary mast cells leading to cardiac events.

OBJECTIVE: Stress precipitates and worsens not only asthma and atopic dermatitis but also acute coronary syndromes (ACSs), which are associated with coronary inflammation. Evidence linking stress to ACS was reviewed and indicated that activation of coronary mast cells (MCs) by stress, through corticotropin-releasing hormone (CRH) and other neuropeptides, contributes to coronary inflammation and coronary artery disease. DATA SOURCES: PubMed was searched (2005-2013) for articles using the following keywords: allergies, anaphylaxis, anxiety, coronary arteries, coronary artery disease, C-reactive protein, cytokines, chymase, histamine, hypersensitivity, interleukin-6 (IL-6), inflammation, mast cells, myocardial ischemia, niacin, platelet-activating factor, rupture, spasm, statins, stress, treatment, tryptase, and uroctortin. STUDY SELECTIONS: Articles were selected based on their relevance to how stress affects ACS and how it activates coronary MCs, leading to coronary hypersensitivity, inflammation, and coronary artery disease. RESULTS: Stress can precipitate allergies and ACS. Stress stimulates MCs through the activation of high-affinity surface receptors for CRH, leading to a CRH-dependent increase in serum IL-6. Moreover, neurotensin secreted with CRH from peripheral nerves augments the effect of CRH and stimulates cardiac MCs to release IL-6, which is elevated in ACS and is an independent risk factor for myocardial ischemia. MCs also secrete CRH and uroctortin, which induces IL-6 release from cardiomyocytes. The presence of atherosclerosis increases the risk of cardiac MC activation owing to the stimulatory effect of lipoproteins and adipocytokines. Conditions such as Kounis syndrome, mastocytosis, and myalgic encephalopathy/chronic fatigue syndrome are particularly prone to coronary hypersensitivity reactions. CONCLUSION: Inhibition of cardiac MCs may be a novel treatment approach.

Rupatadine inhibits inflammatory mediator release from human laboratory of allergic diseases 2 cultured mast cells stimulated by platelet-activating factor.

BACKGROUND: Mast cells are involved in allergy and inflammation by the secretion of multiple mediators, including histamine, cytokines, and platelet-activating factor (PAF), in response to different triggers, including emotional stress. PAF has been associated with allergic inflammation, but there are no clinically available PAF inhibitors. OBJECTIVE: To investigate whether PAF could stimulate human mast cell mediator release and whether rupatadine (RUP), a dual histamine-1 and PAF receptor antagonist, could inhibit the effect of PAF on human mast cells. METHODS: Laboratory of allergic diseases 2 cultured mast cells were stimulated with PAF (0.001, 0.01, and 0.1 µmol/L) and substance P (1 µmol/L) with or without pretreatment with RUP (2.5 and 25 µmol/L), which was added 10 minutes before stimulation. Release of ß-hexosaminidase was measured in supernatant fluid by spectrophotoscopy, and histamine, interleukin-8, and tumor necrosis factor were measured by enzyme-linked immunosorbent assay. RESULTS: PAF stimulated a statistically significant release of histamine, interleukin-8, and tumor necrosis factor (0.001-0.1 µmol/L) that was comparable to that stimulated by substance P. Pretreatment with RUP (25 µmol/L) for 10 minutes inhibited this effect. In contrast, pretreatment of laboratory of allergic diseases 2 cells with diphenhydramine (25 µmol/L) did not inhibit mediator release, suggesting that the effect of RUP was not due to its antihistaminic effect. CONCLUSION: PAF stimulates human mast cell release of proinflammatory mediators that is inhibited by RUP. This action endows RUP with additional properties in treating allergic inflammation.

Perinatal stress, brain inflammation and risk of autism-review and proposal.

BACKGROUND: Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism "susceptibility" genes have been identified, but "environmental" factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. DISCUSSION: We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood-brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with "allergic" or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood-brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. SUMMARY: Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.

Effect of stress on brain inflammation and multiple sclerosis.

Substantial evidence indicates that stress can precipitate or worsen symptoms of inflammation in general and more specifically in multiple sclerosis (MS), a demyelinating, autoimmune disease characterized by inflammation of the central nervous system (CNS). However, the mechanism of how stress affects MS is not well understood. We reviewed publications in PubMed since 1995 and propose that neuropeptides secreted under stress, such as corticotropin releasing hormone (CRH) and neurotensin (NT), activate microglia and mast cells to release inflammatory molecules. These lead to maturation and activation of T17 autoimmune cells, disruption of the blood-brain barrier (BBB) and T cell entry into the CNS, thus promoting brain inflammation and contributing to MS pathology. Reduction of stress and inhibition of these processes by select flavonoids could provide novel therapeutic approaches.